We evaluated the efficacy of humanized anti-interleukin-2 (IL-2) and anti-IL-15 receptor antibodies in the treatment of autoimmune uveoretinitis in nonhuman primates. The inhibitory effect of humanized anti-Tac (HAT), an anti-IL-2R alpha chain Ab, or Hu-Mik-beta-1, an Ab directed at the beta chain shared by the receptor of IL-2 and IL-15, was tested in culture on the proliferative response of monkey lymphocytes stimulated with IL-2 and IL-15. Uveitis was induced in cynomolgus monkey by immunization with human recombinant retinal S-antigen in Hunter's adjuvant. Treatment was initiated at the first sign of disease and consisted of HAT and Hu-Mik-beta-1 alone or in combination, or vehicle control, given by intravenous injection twice a week for four weeks. Disease was evaluated by funduscopy. There was a limited dose-dependent inhibition of the IL-2-driven proliferation of lymphocytes by HAT. Hu-Mik-beta-1 alone was ineffective against IL-2 but had a marked potentiating effect in combination with HAT, independent of IL-15 signaling. IL-15-driven proliferation was inhibited by Hu-Mik-beta-1 but not by HAT alone or in combination. In vivo, the uveitis evolution was significantly improved by HAT treatment. Hu-Mik-beta-1 alone had no effect on disease outcome; however, when used in combination, the 2 Ab reduced the severity of the inflammation, and the effect was sustained for several weeks after cessation of therapy. We conclude that HAT and Hu-Mik-beta-1 antibodies have a promising combination effect for the treatment of severe ocular inflammation.